US7544705B2 - Pyrroloimidazole derivatives, their preparation, pharmaceutical composition containing them, and their use as nootropic agents - Google Patents

Pyrroloimidazole derivatives, their preparation, pharmaceutical composition containing them, and their use as nootropic agents Download PDF

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US7544705B2
US7544705B2 US10/550,483 US55048304A US7544705B2 US 7544705 B2 US7544705 B2 US 7544705B2 US 55048304 A US55048304 A US 55048304A US 7544705 B2 US7544705 B2 US 7544705B2
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pyrrolo
imidazole
dione
tetrahydro
phenyl
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US20070027137A1 (en
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Carlo Farina
Stefania Gagliardi
Carlo Parini
Marisa Martinelli
Carla Ghelardini
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Neurotune AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to new compounds of formula (I) appearing hereinafter, their process of preparation, the pharmaceutical compositions containing them, and their use as nootropic, neuroprotective, analgesic and anti-hyperalgesic agents.
  • the derivatives substituted in position 4 of 2-oxo-1-pyrrolidineacetamide are valid psychotropic agents that re-establish damaged cognitive functions. These compounds are described, for example, in Pharm. Res. Commun. 16, 67, 1984 by Banfi et al. and in Drug Development Res. 2, 447, 1982 by Itil et al.
  • Another chemical class that possesses nootropic activity is represented by imidazolic condensed derivatives, in particular 2,5-dioxohexahydro-1H-pyrrolo[1,2-a]imidazole (dimiracetam), described in EP 335483 and in WO-9309120, and in J. Med. Chem., 36,4214,1993 by Pinza M. et al.
  • nefiracetam could be a good therapeutic agent in the treatment of neuropathic pain.
  • the anti-hyperalgesic action Induced by nefiracetam appears to be of non-opioid nature and is probably due to the stimulation of the nicotinic cholinergic system at a spinal and superspinal level (Rashid Harunor M. D. J. Pharmacol. Exp. Ther, 303, 226, 2002).
  • the present compounds of formula (I) are consequently useful in the treatment of many disorders of the central nervous system (CNS), for example in the deterioration of learning, dysfunctions of the cognitive sphere and of the memory, Alzheimer's disease, dementias, Including senile dementia of the Alzheimer type, post stroke vascular type dementia, epilepsy, cerebral ischaemia, mood disorders, including depression, chronic, inflammatory, neuropathic and visceral pain, and emesis.
  • CNS central nervous system
  • FIGS. 1 a , 1 b non limiting examples of aminoacids of formula (IV), useful in the synthesis of the compounds of formula (I).
  • the encircled portion indicates the substituent R 1 .
  • carbocyclic aromatic group means single or fused aromatic rings with 6 to 12 ring members, optionally substituted.
  • heterocyclic aromatic group and “heterocyclyl” mean single or fused aromatic rings, each ring having 5 to 12 members and comprising up to four hetero atoms, chosen among oxygen, sulphur and nitrogen, optionally substituted.
  • aryl means single or fused unsaturated rings, each ring having from 5 to 8 members, and preferably 5 or 6 members, optionally substituted; by the term “arylC 1-4 alkyl” is Indicated a group having an aryl group, as defined above, and a C 1-4 alkyl moiety connecting the aryl group to the point of substitution.
  • All the aforesaid C 1-4 alkyl groups may be indifferently linear or branched or cyclic (i.e cyclopropyl, cyclopropylmetyl or methylcyclopropyl).
  • Preferred C1-C4 alkyl groups are Me, Et, i-Pr, i-Bu, and cyclopropylmethyl.
  • C 1-7 alkyl groups can either be linear, branched or cyclic, and may include double or triple bonds.
  • C 1-7 alkyl groups interrupted by oxygen or sulphur means, respectively, any ether and thioether groups containing from 1 to 7 carbon atoms.
  • heterocyclylC 1-7 alkyl is indicated a group having an heterocyclyl group, as defined above, and a C 1-7 alkyl moiety connecting the aryl group to the point of substitution.
  • arylC 1-7 alkyl is indicated a group having an aryl group, as defined above, and a C 1-7 alkyl moiety connecting the aryl group to the point of substitution.
  • halogen is meant an atom chosen among fluorine, chlorine, bromine or iodine; by “haloC 1-4 alkyl” is meant a C 1-4 alkyl group substituted at any position by one or more halogen atoms, e.g. trifluoromethyl.
  • “optionally substituted” groups are groups optionally substituted with 1 to 3 substituents, chosen preferably among Me, Et, i-Pr, OH, COOEt, COOH, CH 2 OH, SO 2 NH 2 , SO 2 Me, OMe, Cl, F, CN and CF 3 , and more preferably among Me, Et, i-Pr, OH, CN, Cl and CF 3 ; the substituents may be in any position of the group to be substituted.
  • Preferred compounds according to the invention are the compounds of formula (I), in which A Is a optionally substituted phenyl, optionally substituted benzyl, or else a optionally substituted heterocyclic aromatic group with 5 or 6 members and comprising up to two hetero atoms chosen between oxygen, sulphur and nitrogen, R 1 , R 2 , R 3 and R 4 are chosen among hydrogen, C 1-4 alkyl or benzyl, and n is equal to 2 or 3.
  • A is phenyl, thienyl, pyridyl, pyrimidinyl group, optionally substituted, benzyl or 4methylbenzyl;
  • R 1 is hydrogen, C 1-4 alkyl (for example methyl, isopropyl or isobutyl), benzyl, ⁇ CH 2 OH, —CH 2 CH 2 CONH 2 , —CH 2 COOH, indol(3 yl)methyl,
  • R 2 is hydrogen, C 1-4 alkyl or benzyl,
  • R 3 and R 4 are hydrogen or methyl
  • n is 2.
  • Preferred compounds of formula (I) according to the invention are chosen in the group consisting of:
  • a further subject of the invention is a process for the preparation of the compounds of formula (I), or one of their salts, and/or one of their solvates, comprising the reaction of a compound of formula (II)
  • A-X III in which A, R 1 , R 2 , R 3 , R 4 and n are defined as above for the compounds of formula (I), and X is a halogen atom, chosen preferably between bromine and iodine.
  • the reaction can be carried out in a suitable solvent such as acetonitrile, methylene chloride, acetone, in the presence of a suitable base such as triethylamine, potassium carbonate, 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (also known as BEMP), N,N-Diisopropylethylamine (also known as Hunig base), at a suitable temperature such as reflux temperature (60-140° C., preferably 100° C.).
  • a suitable solvent such as acetonitrile, methylene chloride, acetone
  • a suitable base such as triethylamine, potassium carbonate, 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (also known as BEMP), N,N-Diisopropylethylamine (also known as Hunig base)
  • the compounds of formula (III) are commercially available or can be prepared from known compounds by known methods.
  • the compounds of formula (I) can be prepared with a process comprising the following stages:
  • R 1 , R 2 and A are as defined above for the compound of formula (I), and P is H or a suitable protective group.
  • the activation of aminoacids Is a well-known synthetic procedure; examples of activated derivatives of the aminoacids are mixed anhydrides, acyl chlorides and activated esters.
  • R 1 , R 2 , R 3 , R 4 and n are as defined above for the compound of formula (I), P is defined as above, and R′ is an alkyl group;
  • the alkyl residue R′ is chosen between methyl and tert-butyl
  • P is chosen between hydrogen, a benzyl or a benzyloxycarbonyl group.
  • HBTU O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • an aprotic solvent such as a mixture of acetonitrile (MeCN) and tetrahydrofuran (THF), for example, a mixture with volumetric ratio comprised between 1:9 and 7:3 (MeCN:THF), at any temperature capable of yielding an adequate percentage of formation of the product required, such as a temperature of between ⁇ 70° C. and 50° C., and preferably between ⁇ 10° C. and 25° C.
  • the compounds of formula (VI) and (VII) are preferably reflux-heated in a protic solvent, such as water or methanol, and possibly In the presence of a base, such as NaOH, in the case where the compound of formula (VI) is used in the form of one of its salts obtained by addition of acid, for an adequate period of time, preferably comprised between 2 and 24 hours.
  • a protic solvent such as water or methanol
  • a base such as NaOH
  • Removal of the protective group P by means of hydrogenolysis at stage iii) is preferably conducted using ammonium formate as a source of hydrogen in a suitable protic solvent, such as methanol or a methanol-water mixture.
  • a suitable protic solvent such as methanol or a methanol-water mixture.
  • stage iv) The cyclization reaction in stage iv) Is carried out directly on the compound of formula (VII) coming from stage ii) if P is H, or else, if in said compound (VIII) P is a protective group, the first step is to remove it, as described above in stage iii).
  • the cyclization reaction is conducted in drastic conditions by conventionally heating the compound of formula (VIII) without solvent at 120° C. and in vacuum conditions, or else by means of reflux-heating in xylene for a suitable period of time, for example between 4 hours and 3 days, or by microwave irradiation.
  • the compounds of formula (IV), (V) and (VII) are commercially available compounds or can be prepared from known compounds using known methods.
  • the compounds of formula (IV) can be conveniently selected from any naturally occurring aminoacids or derivatives thereof. Examples of aminoacids useful in the present invention are shown in FIG. 1 , where the part encircled corresponds to the substituent R 1 of formula (IV): accordingly, all these meanings for R 1 are also preferred in formula (I), being the object of the present invention.
  • the present compounds of formula (I) are useful as therapeutic agents and in particular possess a nootropic and neuroprotective activity, i.e., they contribute to restoring the learning and memory functions deteriorated in the process of ageing or on account of ischaemic traumas, and are effective in various pathologies of the CNS, amongst which leaming dysfunctions, dysfunctions of the cognitive sphere and of the memory, Alzheimer's disease, dementias, including senile dementia of the Alzheimer type, post stroke vascular type dementia, epilepsy, cerebral ischaemia, and mood disorders, including depression.
  • the present compounds of formula (I) moreover possess analgesic and/or anti-hyperalgesic activity, i.e., they contribute to combat the sensations of pain, in particular those caused by conditions of neuropathic pain, chronic inflammatory pain and visceral pain, and have proven their efficacy also in the treatment of emesis.
  • the subject of the present invention is hence also the use of the present compounds of formula (I) or of their pharmaceutically acceptable salts and/or solvates for the preparation of medicaments for recovery of difficulties of learning and memory and for treatment of dementias, Alzheimer's disease, post stroke vascular type dementia, epilepsy, cerebral ischaemia, and mood disorders, including depression.
  • the activity of the compounds of formula (I) can be determined in rats in regard to the amnesia-provoking action of scopolamine (D. A. Drachman, Archs. Neurol, Chicago, 30,113, 1974; D. A. Eckerman, Pharmacol. Biochem. Behav. 12, 595, 1980) on the mnemic pathway and on the reduction of the levels of acetylcholine in the hippocampus.
  • the effect on memory and learning can be evaluated in rats using the passive-avoidance test, as described by Essman, Pharmacol. Res. Commun. 5, 295,1973.
  • the subject of the present invention is, moreover, the use of the present compounds of formula (I) or their pharmaceutically acceptable salts or solvates in the treatment of conditions of neuropathic pain, chronic inflammatory pain and visceral pain. Also provided is a method to treat the aforesaid diseases characterised by administering a pharmaceutically active amount of a compound of formula (I) to a patient In need thereof.
  • the activity of the compounds of formula (I) can be determined in mice by means of the thermal-hyperalgesia test (paw-withdrawal test) and the mechanical-hyperalgesia test (paw-pressure test) induced by partial ligation of the sciatic nerve or by treatment with streptozotocine, following the protocols described in J. Pharmacol. Exp. Ther., 303, 226, 2002 and in the bibliography cited therein.
  • the compounds of formula (I) are normally formulated, in compliance with standard pharmaceutical practice, as a pharmaceutical composition.
  • a further subject of the invention is represented by a pharmaceutical composition
  • a pharmaceutical composition comprising, as active principle, a compound of formula (I) or one of its pharmaceutically acceptable salts or solvates, together with vectors, diluents and pharmaceutically acceptable excipients suitable for the chosen form of administration.
  • the compounds of formula (I) can be administered in a standard way in the treatment of the disorders Indicated above, for example via oral, parenteral, rectal, transdermal route or by administration through the mucosa (for example, the sublingual, buccal, or nasal mucosa).
  • the compounds of formula (I) which are administered orally or via sublingual route or via buccal administration can be formulated as syrups, tablets, capsules, and lozenges.
  • a formulation in the form of syrup consists generally of a suspension or solution of the compound or of one of its salts in a liquid vector, for example ethanol, glycerine or water with a flavouring or colouring agent.
  • a liquid vector for example ethanol, glycerine or water with a flavouring or colouring agent.
  • any pharmaceutical vector used conventionally in the preparation of solid formulations examples of said vectors comprise magnesium stereate, starch, lactose and sucrose.
  • any conventional method of encapsulation Is suitable for example using the vectors mentioned above in a capsule of hard gelatine.
  • composition Is in the form of capsules made of soft gelatine it is possible to use any pharmaceutical vector used conventionally in the preparation of dispersions or suspensions, for example aqueous gums, cellulose, silicates or oils, to be Incorporated into a shell made of soft gelatine.
  • a pharmaceutical vector used conventionally in the preparation of dispersions or suspensions, for example aqueous gums, cellulose, silicates or oils, to be Incorporated into a shell made of soft gelatine.
  • Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) in a aqueous or non-aqueous sterile vector, possibly containing an oil acceptable for the parenteral route, for example polyethylene-glycol, polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil.
  • an oil acceptable for the parenteral route for example polyethylene-glycol, polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil.
  • the typical formulation in suppositories comprises a compound of formula (I), which is active if administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatine, cocoa butter, or other low-melting waxes or vegetable fats.
  • a binding and/or lubricating agent for example polymeric glycols, gelatine, cocoa butter, or other low-melting waxes or vegetable fats.
  • Typical transdermal formulations comprise a conventional aqueous or non-aqueous vector, for example cream, ointment; lotion or paste, or can be in the form of medicated plasters, patches or membranes.
  • the composition is in a unit-dose form, for example tablets or capsules, so that the patient can take a single dose.
  • Oxyracetam is a compound used in the treatment of senile dementia and of pathological conditions correlated thereto.
  • the compounds of formula (I) can be administered with regimes similar to the ones established for oxyracetam with any appropriate adjustment of the levels of dosage or of the frequency of dosage in relation to the greater activity and to the better pharmacological profile of the compounds of formula (I).
  • Each dosage unit for oral administration may expediently contain from 0.05 mg/kg to 50 mg/kg, more expediently from 0.1 mg/kg to 25 mg/kg of a compound of formula (I).
  • the active ingredient can be administered from 1 to 6 times a day.
  • the compounds of formula (I) can be co-administered with other pharmaceutically active compounds, for example in association, concurrently or sequentially, in particular together with other compounds used in the treatment of elderly patients, such as tranquilizers, diuretics, anti-hypertensive drugs, vasodilator drugs, and inotropic agents.
  • Rats were anesthetized with chloral hydrate.
  • the common sciatic nerve was exposed at the level of the middle of the thigh by blunt dissection through biceps femoris.
  • Proximal to sciatica's trifurcation about 1 cm of the nerve was freed of adhering tissue and four ligatures (3/0 silk tread) were tied loosely around it with about 1 mm spacing. The length of the nerve thus affected was 1 cm long.
  • Great care was taken to tie the ligatures such that the diameter of the nerve was seen to be just barely constricted when viewed with 40 ⁇ magnification. The left paw was untouched.
  • the nociceptive threshold in the rat was determined with an analgesimeter (Ugo Basile, Varese, Italy), according to the method described by Leighton et al. ( Br. J. Pharmacol. 1988, 93, 553-560). Rats scoring below 40 g or over 75 g during the test before drug administration (25%) were rejected. An arbitrary cut-off value of 250 g was adopted.
  • Gabapentin (30 ⁇ g i.c.v.), levetiracetam (300 ⁇ g i.c.v.), dimiracetam (100 ⁇ g i.c.v.), Example 1 (10 ⁇ g i.c.v.), Example 2 (10 ⁇ g i.c.v.), Example 5 (3 ⁇ g i.c.v.), Example 6 (3 ⁇ g i.c.v.), Example 13 (30 ⁇ g i.c.v.) and Example 22 (30 ⁇ g i.c.v.) of the present invention showed an antihyperalgic effect when compared with saline or vehicle treated group. All componds did not modify pain threshold in controlateral, non operated, paw.

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US20090163565A1 (en) * 2003-03-24 2009-06-25 Carlo Farina Compounds with nootropic action, their preperation, pharmaceutical compositions containing them, and use thereof
US20100062077A1 (en) * 2006-11-15 2010-03-11 Carlo Farina Pyrrolo[1,2-a]imidazoledione effective in the treatment of peripheral neurotoxicity induced by chemotherapeutic agents
US20100099735A1 (en) * 2008-10-16 2010-04-22 Michela Gallagher Methods and compositions for improving cognitive function
US20110212928A1 (en) * 2010-02-09 2011-09-01 The Johns Hopkins University Methods and compositions for improving cognitive function
WO2018219977A1 (en) 2017-05-31 2018-12-06 Metys Pharmaceuticals AG Synergistic compositions comprising (r)-dimiracetam (1) and (s)-dimiracetam (2) in a non-racemic ratio
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
US10159648B2 (en) 2015-05-22 2018-12-25 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam
WO2020115093A1 (en) 2018-12-04 2020-06-11 Metys Pharmaceuticals AG Synergistic compositions comprising (r)-2-(2-oxopyrrolidin-1-yl)butanamide and (s)-2-(2-oxopyrrolidin-1-yl)butanamide in a non-racemic ratio
WO2020115096A1 (en) 2018-12-04 2020-06-11 Metys Pharmaceuticals AG Synergistic compositions comprising r-2-(substituted-sulfonyl)-hexahydro-pyrrolo[1,2-a]pyrazin-6(2h)-ones and s-2-(substituted-sulfonyl)-hexahydro-pyrrolo[1,2-a]pyrazin-6(2h)-ones in a non-racemic ratio
US10806717B2 (en) 2013-03-15 2020-10-20 The Johns Hopkins University Methods and compositions for improving cognitive function
US11160785B2 (en) 2013-03-15 2021-11-02 Agenebio Inc. Methods and compositions for improving cognitive function

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20070770A1 (it) * 2007-04-16 2008-10-17 Brane Discovery S R L Impiego di dimiracetam nel trattamento del dolore cronico
AU2012201853B2 (en) * 2007-04-16 2013-06-27 Neurotune Ag Use of dimiracetam in the treatment of chronic pain
US9125898B2 (en) 2008-11-14 2015-09-08 Neurotune Ag Acetam derivatives for pain relief
PL2598504T3 (pl) * 2010-07-26 2014-10-31 Neurotune Ag Sposób otrzymywania dimiracetamu

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0174136A1 (en) 1984-08-24 1986-03-12 Warner-Lambert Company Derivatives of dihydro-1H-pyrrolo(1,2-c)imidazol-3,5-dione as cognition activators
EP0335483A2 (en) 1988-02-08 1989-10-04 Isf Societa Per Azioni Condensed imidazole derivatives, process and intermediates for their preparation and pharmaceutical compositions containing them.
WO1993009120A1 (en) 1991-11-07 1993-05-13 Smithkline Beecham Farmaceutici S.P.A. Process for the preparation of condensed imidazoles

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5200406A (en) * 1988-02-08 1993-04-06 I.S.F. Societa Per Azioni Pharmaceutically useful 2,5-dioxo-1H-octahydroimidazo[1,2-A]azepines
JP3400466B2 (ja) * 1991-10-28 2003-04-28 日本水産株式会社 高純度エイコサペンタエン酸またはそのエステルの製造方法
ITMI20030573A1 (it) * 2003-03-24 2004-09-25 Nikem Research Srl Composti ad azione nootropica, loro preparazione,
EP1925304A1 (en) * 2006-11-15 2008-05-28 Nikem Research S.R.L. Pyrrolo[1,2-a]imidazoledione effective in the treatment of peripheral neurotoxicity induced by chemotherapeutic agents

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0174136A1 (en) 1984-08-24 1986-03-12 Warner-Lambert Company Derivatives of dihydro-1H-pyrrolo(1,2-c)imidazol-3,5-dione as cognition activators
EP0335483A2 (en) 1988-02-08 1989-10-04 Isf Societa Per Azioni Condensed imidazole derivatives, process and intermediates for their preparation and pharmaceutical compositions containing them.
US5053422A (en) * 1988-02-08 1991-10-01 I.S.F. Societa Per Azioni Psychotropic perhydroazacycloalka [1,2-A] imidazole derivatives
US5130319A (en) * 1988-02-08 1992-07-14 I.S.F. Societa Per Azioni Pharmacologically active 2,5-dioxo-octahydro-imidazo [1,2-a]pyridines
WO1993009120A1 (en) 1991-11-07 1993-05-13 Smithkline Beecham Farmaceutici S.P.A. Process for the preparation of condensed imidazoles

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Mario Pinza et al., "Synthesis and Pharmacological Activity of a Series of Dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones, a Novel Class of Potent Cognition Enhancers", J. Med. Chemistry, vol. 36, pp. 4214-4220 (1993).

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7732473B2 (en) * 2003-03-24 2010-06-08 Neurotune Ag Compounds with nootropic action, their preparation, pharmaceutical compositions containing them, and use thereof
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US20090163565A1 (en) * 2003-03-24 2009-06-25 Carlo Farina Compounds with nootropic action, their preperation, pharmaceutical compositions containing them, and use thereof
US20100062077A1 (en) * 2006-11-15 2010-03-11 Carlo Farina Pyrrolo[1,2-a]imidazoledione effective in the treatment of peripheral neurotoxicity induced by chemotherapeutic agents
US7973066B2 (en) * 2006-11-15 2011-07-05 Neurotune Ag Pyrrolo[1,2-A]imidazoledione effective in the treatment of peripheral neurotoxicity induced by chemotherapeutic agents
US8604075B2 (en) 2008-10-16 2013-12-10 The Johns Hopkins University Methods and compositions for improving cognitive function
US20100099735A1 (en) * 2008-10-16 2010-04-22 Michela Gallagher Methods and compositions for improving cognitive function
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US10159648B2 (en) 2015-05-22 2018-12-25 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam
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